ABSTRACT
PURPOSE: The zeta isozyme of protein kinase C (PKC) is essential for activation of the transcription factor nuclear factor (NF)kappaB and transcription of vascular endothelial growth factor (VEGF). This study examined the antiangiogenic potential of an existing drug, pentoxifylline (PTX), which inhibits PKC-dependent activation of NFkappaB and is reported to prevent hypoxia-induced expression of VEGF. METHODS: Neovascularization was induced by maintaining neonatal rats for 10 full days in 80% oxygen, interrupted daily by 30 minutes in room air followed by a progressive return to 80% oxygen. On experimental day 11, they were placed in room air until they were killed on day 17. Daily intraperitoneal injections of PTX in saline (25 or 75 mg/kg per day), or saline alone, were administered from day 6 through day 16. Retinal neovascularization was scored, and avascular areas (AVAs) were measured in ADPase stained retinas. RESULTS: PTX inhibited radial extension of retinal vessels, causing increases in AVA of 65% (P < 0.01) and 33% (P < 0.15) at the lower and upper doses, respectively. A significant increase in mean neovascular score was seen at the lower dose (P < 0.0001), but analysis of variance indicated that neovascularization was strongly and positively influenced by the AVA (P < 0.0001) and only weakly stimulated by PTX (P < 0.05). CONCLUSIONS: Systemic PTX significantly inhibited VEGF-mediated retinal vasculogenesis, but was not effective in reducing neovascularization in the oxygen-exposed neonatal rat.
